Benzimidazole compounds

ABSTRACT

This invention relates to compounds useful in treating HT 4  and/or HT 3  mediated conditions of the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino; R 3  is selected from the group consisting of H, alkyl and cycloalkyl; X is NH or O; Z is selected from the group consisting of ##STR2## n and r are independently 1 or 2; p is 0 or 1; pharmaceutical compositions containing the compounds and a method for treating serotonin mediated condition with the compositions which act as 5-HT 4  agonists or antagonists and/or 5-HT 3  antagonists.

BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical agents (compounds) which act as 5-HT₄ agonists or antagonists and/or 5-HT₃ antagonists in mammals. As 5-HT₄ agonists these agents are useful in the treatment of hypomotility disorders of the gastrointestinal (GI) tract including reflux esophagitis, non-ulcer dyspepsia, gastroparesis, ileus, irritable bowel syndrome (constipation predominant) and constipation. Additionally, 5-HT₄ agonists are useful for the treatment of learning and memory disorders and as cardiovascular inotropic agents. As 5-HT₄ antagonists these compounds are useful in the treatment of motility disorders of the GI tract such as diarrhea and irritable bowel syndrome (diarrhea predominant). As 5-HT₃ antagonists these compounds are useful for treating emesis (caused by cancer chemotherapy or post-operative), anxiety, cognitive disorders, drug abuse (either cravings or withdrawal syndrome) and irritable bowel syndrome (diarrhea predominant).

Serotonin (5-hydroxytryptanine; 5-HT) functions as a neurotransmitter in the mammalian central nervous system (CNS) and in the periphery. Serotonergic neurons regulate a wide variety of sensory, motor and cortical functions. Additionally serotonin regulates enteric reflexes, mediates contraction of the vascular smooth muscle and platelet shape change and aggregation and as such effects such diverse systems as the cardiovascular system and gastrointestinal system, in addition to the central nervous system.

Pharmacological and physiological studies show that the activity of serotonin is mediated by several distinct cell surface receptor subtypes. These receptor subtypes either transduce extracellular signals by activating GTP-binding proteins (G-protein-coupled receptor subtypes) or activate the opening of nonselective cation channels to promote fast, depolarizing responses in neurons (ligand-gated ion channel receptor subtypes). 5-HT₄ belongs to the former category while 5-HT₃ belongs to the latter. Agents which interact with these receptors thereby modulate a variety of ion channels and intracellular messenger signaling pathways thereby extending the flexibility of serotonings activity and eliciting a multitude of cellular and physiological responses. P. Bonate, Clinical Neuropharmacology, Vol. 14, No. 1, pp. 1-16 (1991).

European Patent application 309,423 discloses azabicyclo substituted benzimidazoline-2-oxo-1-carboxylic acid derivatives which are useful as 5-HT receptor antagonists.

Dumuis et al., Nauyn-Schmiedeberg's Arch Pharmacol, (1991) 343:245-251 disclose azabicycloalkyl benzimidazolone derivatives as potent agonists at the 5-HT₄ receptor.

In Pharmacological Research, Vol. 22, Supplement 2, (1990) Schiantarelli et al. disclose two benzimidazolone compounds useful as 5-HT₃ antagonists and 5-HT₄ agonists.

There is a need in the area of serotonin regulation for agents with broad clinical usefulness. Serotonin is one of the newer neurotransmitters to be recognized for physiological importance and agents which interact with 5-HT receptors are currently the focus of much research. P. Bonate, Clinical Neuropharmacology, Vol. 14, No. 1, pp. 1-16 (1991). Accordingly, it is the object of this invention to produce compounds for use as pharmaceutical agents which will exhibit 5-HT₄ agonist or antagonist activity and/or 5-HT₃ antagonist activity in mammals. The compounds of the present invention meet the need for an agent which has broad clinical usefulness for treating serotonin mediated conditions in mammals by administering a therapeutically effective amount of the compounds to act as 5-HT₄ agonists or antagonists and/or 5-HT₃ antagonists.

SUMMARY OF THE INVENTION

This invention relates to compounds of the Formula I ##STR3## or a pharmaceutically acceptable salt thereof

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino;

R₃ is selected from the group consisting of H, alkyl and cycloalkyl;

X is NH or O;

Z is selected from the group consisting of ##STR4##

n and r are independently 1 or 2; and

p is 0 or 1.

The present invention also provides pharmaceutical compositions comprised of a therapeutically effective amount of the compounds of Formula I in combination with a pharmaceutically acceptable carrier and a method for treating serotonin mediated conditions with said compositions which act as 5-HT₄ agonists or antagonists and/or 5-HT₃ antagonists.

DETAILED DESCRIPTION OF THE INVENTION

This invention encompasses compounds of the Formula I as previously described.

Within the class of compounds defined by Formula I, there is a sub-class of preferred compounds represented by Formula II: ##STR5## or a pharmaceutically acceptable salt thereof

wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino;

R₃ is selected from the group consisting of H, alkyl and cycloalkyl;

Z is selected from the group consisting of ##STR6##

n and r are independently 1 or 2; and

p is 0 or 1.

A more preferred subclass of compounds included within Formula II are:

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide;

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide;

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide;

cis-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide;

5-chloro-N-[2-(hexahydro-7aH-pyrrolizin-7a-yl)ethyl]-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide;

N-[2-(hexahydro-7aH-pyrrolizin-7a-yl)ethyl]-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide; and

N-[(hexahydro-7aH-pyrrolizin-7a-yl)methyl]-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

6-fluoro-N-[2-(hexahydro-7aH-pyrrolizin-7a-yl)ethyl]-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

N-[2-(hexahydro-7aH-pyrrolizin-7a-yl)ethyl]-2,3-dihydro-6-methoxy-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

3-ethyl-N-[2-(hexahydro-7aH-pyrrolizin-7a-yl)ethyl]-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.

N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta [c]pyrrol-4α-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide

Included within the classes and subclasses of compounds embraced by Formulas I-II are isomeric forms of the described compounds including diastereoisomers and enantiomers and tautomeric forms of the described compounds. Pharmaceutically acceptable salts of such compounds are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.

In the structures herein a bond drawn across a bond in a ring indicates that the bond can be to any available atom of the ring structure.

The term "pharmaceutically acceptable salt," as used herein, refers to conventionally accepted pharmaceutical salts prepared by processes which are well known to those of ordinary skill in the art. [See for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977)).

The term "composition" as used herein means a product which results from the mixing or combining of more than one element or ingredient.

The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, exciplent, solvent or encapsulating material, involved in carrying or transporting a chemical agent from one organ or portion of the body to another organ or portion of the body.

The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.

The term "alkyl" as used herein means a univalent hydrocarbon radical having from one to twelve carbon atoms, more preferably from one to six carbon atoms and derived by the removal of a single hydrogen atom from a straight or branched chain saturated hydrocarbon. Representative of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylhexyl, n-octyl, 2,4-dimethylpentyl and the like.

The term "alkoxy" as used herein means an alkyl radical, as defined above having one or more oxygen atoms attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term halogen as used herein means a fluoro, chloro, bromo or iodo radical.

The term "monoalkylazino" as used herein is represented by the radical --NHR₄ wherein R₄ is an alkyl group as previously described.

The term "dialkylazino" as used herein is represented by the radical --NR₄ R₅ wherein R₄ and R₅ are the same or different alkyl groups, as defined above.

The term "acylamino" as used herein is represented by the radical ##STR7## wherein R₄ is an alkyl group as described above.

The term "alkylsulfonylanino" as used herein is represented by the radical R₄ --SO₂ --NH-- wherein R₄ is an alkyl group as defined above.

The term "cycloalky" as used herein means an alicyclic radical with from 3 to 6 carbon atoms. Examples of suitable cycloalkyl radicals includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl and the like.

The compounds herein exhibit 5-HT₄ agonism or antagonism and/or 5-HT₃ antagonism. The 5-HT₃ antagonist activity possessed by the compounds of this invention was determined by the radioligand receptor binding assay as described herein and in the in vivo Bezold-Jarisch reflex procedure. 5-HT₄ agonist activity was determined in the in vitro rat tunica muscularis mucosas (TMM) assay. (Baxter et al., Naunyn Schmied Arch. Pharmacol, 1991, 343, 439). The 5-HT₄ agonist or antagonist activity and/or 5-HT₃ antagonist activity of the compounds of the invention herein, can be determined by the assays as described herein, without undue experimention.

By virtue of their activity as 5-HT₄ agonists or antagonists and/or 5-HT₃ antagonists the compounds of Formula I and II are useful in treating serotonin mediated conditions such as gastrointestinal motility disorders, emesis, anxiety, cognitive disorders and other CNS disorders. As used herein 5-HT₄ agonist mediated conditions of the gastrointestinal tract include reflux esophagitis, non-ulcer dyspepsia, gastroparesis, ileus, irritable bowel syndrome (constipation predominant), constipation, and the like. As used herein 5-HT₄ antagonist mediated conditions of the GI tract include diarrhea, irritable bowel syndrome (diarrhea predominant) and the like. As used herein 5-HT₃ antagonist mediated conditions include emesis due to either cancer chemotherapy or post-operative, anxiety, cognitive disorders, drug abuse (either cravings or withdrawal syndrome), irritable bowel syndrome (diarrhea predominant) and the like. A physician or veterinarian of ordinary skill can readily determine whether a subject exhibits such a serotonin mediated condition.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules, softgels, pills, powders, granules, elixirs or syrups. The compounds can also be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically using forms known to the pharmaceutical art. In general the preferred form of administration is oral.

For the orally administered pharmaceutical compositions and methods of the present invention, the foregoing active ingredients will typically be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to hereinafter as "carrier" materials). Such carrier materials are suitably selected with respect to the intended form of administration and consistent with conventional pharmaceutical practices.

For example, for oral administration in the form of tablets or capsules, a therapeutically effective amount of one or more compounds of the present invention can be combined with any oral pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, calcium sulfate and the like or various combinations thereof. For oral administration in liquid forms, such as in softgels, elixirs, syrups and the like, a therapeutically effective amount of the active drug components can be combined with any oral pharmaceutically acceptable inert carrier such as water, ethanol, polyethylene glycol, vegetable oils, propylene glycol, benzylalcohol and the like or various combinations thereof.

When desired or necessary, suitable binders, lubricants, disintegrating agents, preservatives, and coloring or flavoring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums and waxes and the like, or combinations thereof. Lubricants can include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like, or combinations thereof. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, guar gum and the like, or combinations thereof.

For intravascular, intraperitoneal, subcutaneous or intramuscular administration, one or more compounds of the present invention can be combined with a suitable carrier such as water, saline, aqueous dextrose and the like. For topical administration therapeutically effective amounts of one or more compounds of the present invention can be combined with pharmaceutically acceptable creams, oils, waxes, gels and the like.

Regardless of the route of administration selected, a therapeutically effective amount of the compounds of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The dosages for preventing or treating serotonin mediated conditions with the compounds of the present invention is determined in accordance with a variety of factors, including the type, age, weight, sex and medical condition of patient, the severity of the condition, the route of administration and the particular compound employed in the treatment. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of drug required to prevent or arrest progress of the condition. In so proceeding, the physician or veterinarian could employ relatively low doses at first and subsequently increase the dose until a maximum response is obtained. The daily doses of the compounds of the invention are ordinarily in the range of about 1 to 1000 mg, more preferably in the range of about 10 to 500 mg.

The compounds of this invention are generally prepared according to reaction schemes I and II. ##STR8##

As shown in reaction Scheme I the 3-unsubstituted benzimidazolones A are reacted with a base (preferably sodium hydride) in an inert etheral solvent (preferably tetrahydrofuran) to generate the sodium salt, which is reacted with phosgene to produce the 3-carbamoylchloride substituted benzimidazolone B. This intermediate is reacted with the appropriate amine (Z-NH₂, as defined above) in an inert solvent (preferably tetrahydrofuran) in the presence of a base (preferably triethylamine) to afford the desired compounds of formulae II.

Alternatively, as shown in reaction Scheme II, intermediate B is reacted with the appropriate alcohol (Z-OH, as defined above) or its metal salt (preferably Na, K, or Cs; formed by reaction with, by illustration, sodium hydride, potassium hydride, cesium carbonate) in an inert solvent (preferably tetrahydrofuran or dimethylformamide) at either ambient or elevated temperature (50° C. to 110° C.) to afford desired compounds of formulae I, wherein X=O.

The following examples illustrate the methods used to prepare the compounds of this invention. These examples are given by way of illustration only and are not meant to be construed as limiting the invention in spirit or scope, as many modifications in materials and methods will be apparent from this disclosure to one having ordinary skill in the art.

EXAMPLE 1 ##STR9##

5-chloro-2-nitroaniline (8.6 g; 0.05 mole), 2,2-dimethoxypropane (10.0 ml; 0.09 mole) and trifluoroacetic acid [TFA] (4.0 ml; 0.005 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. A boron/pyridine complex (hereinafter BH₃ * pyridine) (5.0 ml; 0.05 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc (40%EtOAc/hexane). Additional TFA, BH₃ * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 5-chloro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with toluene. The product was the first major component to elute, which produced 6.6 g (61%) of a yellow crystalline solid.

C₉ H₁₀ ClN₂ O₂ M.W. 213.63.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           50.36  50.27                                                  Hydrogen         5.17   5.17                                                   Nitrogen         13.05  12.97                                                  Chlorine         16.52  15.92                                                  ______________________________________                                    

EXAMPLE 2 ##STR10##

5-chloro-N-isopropyl-2-nitroaniline (6.5 g; 0.03 mole) was dissolved in MeOH (330 ml) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 1.5 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (250 ml) and triphosgene (3.06 g; 0.01 mole) dissolved in 25 ml of CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. and then concentrated. The residue was placed on a bed of silica and eluted with EtOH/CH₂ Cl₂ using a gradient from 5%→>40% EtOH. The fractions containing the product were combined and concentrated to yield 2.7 g (43%) of a purple-white solid.

C₁₀ H₁₁ ClN₂ O M.W. 210.65.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.01  56.61                                                  Hydrogen         5.26   5.29                                                   Nitrogen         13.30  13.19                                                  Chlorine         16.83  17.20                                                  ______________________________________                                    

EXAMPLE 3 ##STR11##

4-chloro-2-nitroaniline (8.6 g; 0.05 mole), 2,2-dimethoxypropane (10.0 ml; 0.9 mole) and trifluoroacetic acid [TFA] (4.0 ml; 0.005 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. BH₃ * pyridine (5.0 ml; 0.05 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40%EtOAc/Hexane. Additional TFA, BH₃ * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-chloro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with toluene. The product was the first major component to elute, which produced 8.4 g (78%) of a yellow crystalline solid.

C₉ H₁₀ ClN₂ O₂ M.W. 213.63.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           50.36  50.44                                                  Hydrogen         5.17   5.26                                                   Nitrogen         13.05  12.96                                                  Chlorine         16.52  16.22                                                  ______________________________________                                    

EXAMPLE 4 ##STR12##

4-chloro-N-isopropyl-2-nitroaniline (8.3 g; 0.0389 mole) was dissolved in MeOH (330 ml) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 1.5 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (250 ml) and triphosgene (3.9 g; 0.014 mole) dissolved in 25 ml of CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. and then concentrated. The solid was triturated with water and filtered, washed with Et₂ O and suction dried which produced 5.7 g (69.5%) of a purple-white solid.

C₁₀ H₁₁ ClN₂ O M.W. 210.65.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.01  56.89                                                  Hydrogen         5.26   5.28                                                   Nitrogen         13.30  13.29                                                  Chlorine         16.83  16.54                                                  ______________________________________                                    

EXAMPLE 5 ##STR13##

5-chloro-2-nitroaniline (17.2 g; 0.1 mole), acetalaldehyde diethyl acetal (Acetal) (21.1 ml; 0.15 mole) and TFA (7.7 ml; 0.1 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH₃ * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40%EtOAc/Hexane. Additional TFA, BH₃ * pyridine and acetal were added until the tlc indicated that the 5-chloro-2-nitroaniline was consumed. The reaction mixture was washed 2X with water and placed on a bed of silica and eluted with toluene. The product was the first major component to elute. The product was crystallized from MeOH which produced 17.6 g (88%) of a yellow crystalline solid.

C₈ H₉ ClN₂ O₂ M.W. 200.63.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           47.89  47.69                                                  Hydrogen         4.52   4.36                                                   Nitrogen         13.96  13.92                                                  Chlorine         17.67  17.71                                                  ______________________________________                                    

EXAMPLE 6 ##STR14##

5-chloro-N-ethyl-2-nitroaniline (17.6 g; 0.0877 mole) was dissolved in MeOH (1.0 l) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 1.9 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (500 ml) and triphosgene (8.6 g; 0.029 mole) dissolved in 50 ml of CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. and then concentrated. The solid was triturated with water and filtered, washed with Et₂ O and suction dried which produced 7.9 g (46%) of a blue-white solid.

C₉ H₉ ClN₂ O M.W. 196.64.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           52.57  52.18                                                  Hydrogen         4.90   4.68                                                   Nitrogen         13.62  13.68                                                  Chlorine         17.24  17.17                                                  ______________________________________                                    

EXAMPLE 7 ##STR15##

4-chloro-2-nitroaniline (8.6 g; 0.05 mole), acetaldehyde (5.5 ml; 0.05 mole) and HOAc (4.0 ml; 0.1 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. BH₃ * pyridine (5.0 ml; 0.01 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc (40%EtOAc/Hexane). Additional TFA, BH₃ * pyridine and acetaldehyde were added until the tlc indicated that the 4-chloro-2-nitroaniline was consumed. The reaction mixture was washed 2X with water and placed on a bed of silica and eluted with 20% EtOAc/Hexane. The product was the first major component to elute. The product was crystallized from MeOH which produced 5.0 g (50%) of a yellow crystalline solid.

C₈ H₉ ClN₂ O₂ M.W. 200.63.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           47.89  47.57                                                  Hydrogen         4.52   4.41                                                   Nitrogen         13.96  14.07                                                  Chlorine         17.67  17.77                                                  ______________________________________                                    

EXAMPLE 8 ##STR16##

4-chloro-N-ethyl-2-nitroaniline (8.7 g; 0.0436 mole) was dissolved in MeOH (330 ml) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 3.1 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (200 ml) and triphosgene (4.3 g; 0.0145 mole) dissolved in 25 ml of CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. then concentrated. The solid was triturated with water and filtered, washed with Et₂ O and suction dried which produced 5.5 g (64%) of a blue-white solid.

C₉ H₉ ClN₂ O M.W. 196.64.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           52.57  52.83                                                  Hydrogen         4.90   4.90                                                   Nitrogen         13.62  13.74                                                  Chlorine         17.24  17.21                                                  ______________________________________                                    

EXAMPLE 9 ##STR17## This compound was prepared by the methodology of E. A. Watts, in U.S. Pat. No. 4,816,453 (1989). EXAMPLE 10 ##STR18## This compound was prepared by the method of D. L. Flynn et al., J. Med. Chem., 35, 1486 (1992). EXAMPLE 11 ##STR19## This compound was prepared by the methodology of E. A. Watts, in U.S. Pat. No. 4,816,453 (1989). EXAMPLE 12 ##STR20##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 6-chloro-1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (105 mg; 0.0005 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-(2-aminoethyl)hexahydro-1H-pyrrolizine [the Journal of Heterocyclic Chemistry, 24, 271 (1987)) (77 mg; 0.0005 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed first on a 2 mm Chromatron plate, and the semi-purified fraction containing the product was rechromatographed on a prep tlc plate, in both cases eluting with 20%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 51 mg (26%) of product was isolated. The product was converted to the HCl salt by dissolving 11.1 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₀ H₂₇ ClN₄ O₂ * 1.2 HCl M.W. 437.67.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           55.27  55.57                                                  Hydrogen         6.54   6.42                                                   Nitrogen         12.89  12.89                                                  Chlorine         17.94  17.88                                                  ______________________________________                                    

EXAMPLE 13 ##STR21##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (176 mg; 0.001 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-(2-aminoethyl)hexahydro-1 H-pyrrolizine (77 mg; 0.0005 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 20%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 149 mg (83.7%) of product was isolated. The product was converted to the HCl salt by dissolving 35.6 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₀ H₂₈ N₄ O₂ * 1.2 HCl 0.25 H₂ O M.W. 437.67.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           59.21  58.94                                                  Hydrogen         7.63   7.27                                                   Nitrogen         13.78  13.78                                                  Chlorine         10.49  10.25                                                  ______________________________________                                    

EXAMPLE 13A ##STR22##

60% NaH/Mineral oil (80 mg; 0.002) was washed with hexane and suspended in THF. 6-fluoro-1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (145 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-(2-aminoethyl) hexahydro-1H-pyrrolizine [the Journal of Heterocyclic Chemistry, 24, 271 (1987)] (77 mg; 0.0005 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed first on a 2 mm Chromatron plate, and the semi-purified fraction containing the product was rechromatographed on a prep tlc plate, in both cases eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 105 mg (56%) of product was isolated. The product was converted to the HCl salt by dissolving 11.1 gl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, and then concentrating to dryness.

C₂₀ H₂₇ FN₄ O₂ *1.1 HCl*H₂ O M.W. 432.58.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           55.53  55.62                                                  Hydrogen         7.01   7.01                                                   Nitrogen         12.95  12.91                                                  Chlorine         9.02   9.35                                                   ______________________________________                                    

EXAMPLE 13B ##STR23##

60% NaH/Mineral oil (8 mg; 0.002) was washed with hexane and suspended in THF. 1,3-dihydro-6-methoxy-1-(1-methylethyl)-2H-benzimidazol-2-one (154 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-(2-aminoethyl)hexahydro-1H-pyrrolizine [the Journal of Heterocyclic Chemistry, 24, 271 (1987)] (77 mg; 0.0005 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed first on a 2 mm Chromatron plate, and the semi-purified fraction containing the product was rechromatographed on a prep tlc plate, in both cases eluting with 10% MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5% NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 118 mg (61%) of product was isolated. The product was converted to the HCl salt by dissolving 11.1 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₁ H₃₀ N₄ O₃ HCl * 1.25 H₂ O M.W. 445.48.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           56.62  56.64                                                  Hydrogen         7.58   7.48                                                   Nitrogen         12.58  12.52                                                  Chlorine         7.96   7.74                                                   ______________________________________                                    

EXAMPLE 13C ##STR24##

60% NaH/Mineral oil (80 mg; 0.002) was washed with hexane and suspended in THF. 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (121 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 204 phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-(2-aninoethyl) hexahydro-1H-pyrrolizine [the Journal of Heterocyclic Chemistry, 24, 271 (1987)] (77 mg; 0.0005 mole) was added with 0.5 μl of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10% MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5% NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 147 mg (86%) of product was isolated. The product was converted to the HCl salt by dissolving 16 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₆ N₄ O₂ * 1.25 H₂ O M.W. 380.53.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           59.97  59.69                                                  Hydrogen         6.65   6.52                                                   Nitrogen         14.72  14.67                                                  Chlorine         10.25  10.40                                                  ______________________________________                                    

EXAMPLE 14 ##STR25##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (176 mg; 0.001 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and 7a-aminomethylhexahydro-1H-pyrrolizine [the Journal of Heterocyclic Chemistry, 24, 47(1987)] (70 mg; 0.0005 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 149 mg (83.7%) of product was isolated. The product was converted to the HCl salt by dissolving 35.6 gl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₆ N₄ O₂ * 1.15 HCl 0.5 H₂ O M.W. 394.39.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.86  57.88                                                  Hydrogen         7.45   7.07                                                   Nitrogen         14.21  13.83                                                  Chlorine         10.13  10.13                                                  ______________________________________                                    

EXAMPLE 15 ##STR26##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (121 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 184 mg (74%) of product was isolated. The product was converted to the HCl salt by dissolving 16 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₄ N₄ O₂ * 1.1 HCl M.W. 380.53.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           59.97  59.69                                                  Hydrogen         6.65   6.52                                                   Nitrogen         14.72  14.67                                                  Chlorine         10.25  10.40                                                  ______________________________________                                    

EXAMPLE 16 ##STR27##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 5-chloro-1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (157 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 184 mg (74%) of product was isolated. The product was converted to the HCl salt by dissolving 26 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₀ N₂₅ ClN₄ O₂ * 1.05 HCl 0.5 H₂ O M.W. 436.19.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           55.07  55.27                                                  Hydrogen         6.25   5.98                                                   Nitrogen         12.84  12.85                                                  Chlorine         16.66  16.87                                                  ______________________________________                                    

EXAMPLE 17 ##STR28##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 6-chloro-1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (157 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 150 mg (53%) of product was isolated. The product was converted to the HCl salt by dissolving 30 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₀ H₂₅ ClN₄ O₂ * HCl H₂ O M.W. 443.38.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           54.18  54.38                                                  Hydrogen         6.37   6.06                                                   Nitrogen         12.64  12.66                                                  Chlorine         15.99  16.27                                                  ______________________________________                                    

EXAMPLE 18 ##STR29##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 5-chloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (147 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 200 mg (73%) of product was isolated. The product was converted to the HCl salt by dissolving 42 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₃ ClN₄ O₂ * HCl * 0.75 M.W. 422.05.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           54.07  54.26                                                  Hydrogen         5.83   5.83                                                   Nitrogen         13.27  13.24                                                  Chlorine         15.12  15.15                                                  ______________________________________                                    

EXAMPLE 19 ##STR30##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 6-chloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (147 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 181 mg (66%) of product was isolated. The product was converted to the HCl salt by dissolving 38 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₃ ClN₄ O₂ * 0.9 HCl * H₂ O M.W. 425.70.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           53.61  53.79                                                  Hydrogen         5.75   5.75                                                   Nitrogen         13.16  13.11                                                  Chlorine         15.82  15.54                                                  ______________________________________                                    

EXAMPLE 19A ##STR31##

60% NaH/Mineral oil (80 mg; 0.002) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (132 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in example 9 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10% MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5% NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 118 mg (46%) of product was isolated. The product was converted to the HCl salt by dissolving 16 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₂₀ H₂₆ N₄ O₂ * 1.1 HCl * 1.25 H₂ O M.W. 417.08.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.60  57.92                                                  Hydrogen         7.15   6.88                                                   Nitrogen         13.43  13.39                                                  Chlorine         9.35   9.26                                                   ______________________________________                                    

EXAMPLE 20 ##STR32##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (121 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 11 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr. filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 160 mg (64.5%) of product was isolated. The product was converted to the HCl salt by dissolving 36 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ N₂₄ N₄ O₂ * 1.1 HCl * 1.25 H₂ O M.W. 403.05.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           56.62  56.40                                                  Hydrogen         6.90   6.71                                                   Nitrogen         13.90  13.70                                                  Chlorine         9.68   9.34                                                   ______________________________________                                    

EXAMPLE 21 ##STR33##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 5-chloro-1,3-dihydro-1-ethyl-2H-benzimidazol-2-one (147 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 11 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 149 mg (54%) of product was isolated. The product was converted to the HCl salt by dissolving 31 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₃ ClN₄ O₂ * HCl H₂ O 0.75 MeOH M.W. 453.38.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           52.32  52.69                                                  Hydrogen         6.45   6.18                                                   Nitrogen         12.36  12.36                                                  Chlorine         15.64  15.42                                                  ______________________________________                                    

EXAMPLE 22 ##STR34##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 6-chloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (147 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 11 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 186 mg (68%) of product was isolated. The product was converted to the HCl salt by dissolving 39 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₃ ClN₄ O₂ * HCl * H₂ O M.W. 429.35.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           53.15  53.18                                                  Hydrogen         6.10   5.79                                                   Nitrogen         13.05  12.93                                                  Chlorine         16.51  16.16                                                  ______________________________________                                    

EXAMPLE 22A ##STR35##

60% NaH/Mineral oil (80 mg; 0.002) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (132 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 11 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10% MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5% NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 194 mg (75%) of product was isolated. The product was converted to the HCl salt by dissolving 16 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product and then concentrating to dryness.

C₂₀ H₂₆ N₄ O₂ * 1.5 HCl * 1.75 H₂ O M.W. 440.67.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           54.51  54.41                                                  Hydrogen         7.09   6.98                                                   Nitrogen         12.71  12.47                                                  Chlorine         12.07  11.76                                                  ______________________________________                                    

EXAMPLE 22B ##STR36##

60% NaH/Mineral oil (80 mg; 0.002) was washed with hexane and suspended in THF. 5-chloro-1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (157 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 11 (104 mg; 0.00075 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10% MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5% NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 214 mg (76 %) of product was isolated. The product was converted to the HCl salt by dissolving 26 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product and then concentrating to dryness.

C₂₀ H₂₅ CIN₄ O₂ * 1.2 HCl * 2 H₂ O M.W. 468.68.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           51.25  51.19                                                  Hydrogen         6.49   6.13                                                   Nitrogen         11.95  11.85                                                  Chlorine         16.64  16.61                                                  ______________________________________                                    

EXAMPLE 23 ##STR37##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (176 mg; 0.001 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and the compound prepared in Example 10 (140 mg; 0.001 mole) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 30%MeOH/CHCl₃ /0.25%NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 157 mg (50%) of product was isolated. The product was converted to the HCl salt by dissolving 36 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ N₂₆ N₄ O₂ * HCl * H₂ O M.W. 396.92.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.50  57.44                                                  Hydrogen         7.32   7.42                                                   Nitrogen         14.12  13.87                                                  Chlorine         8.93   8.93                                                   ______________________________________                                    

EXAMPLE 24 ##STR38##

60% NaH/Mineral oil (80 mg; 0.002 mole) was washed with hexane and suspended in THF. 1,3-dihydro-1-(1-methylethyl)-2H-benzimidazol-2-one (132 mg; 0.00075 mole) was added to the suspension. This mixture was stirred 15 minutes before adding to a mixture of 2.5 ml (0.004 mole) 20% phosgene in toluene/2.5 ml THF. The resulting mixture was filtered through celite and concentrated. The residue was dissolved in THF (5.0 ml) and N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4α-yl)amine (80 mg; 0.000578 mole) [prepared according to method of Becker et al., EP 454,121) was added with 0.5 ml of Et₃ N. This mixture was stirred 1 hr., filtered and the filtrate concentrated. The residue was chromatographed on a prep tlc plate, eluting with 10%MeOH/CHCl₃ /0.25 NH₄ OH. The product was washed from the silica with 5%NH₄ OH/MeOH. The filtrate was concentrated and the residue was dissolved in CHCl₃ and filtered through celite and concentrated. 115 mg (59%) of product was isolated. The product was converted to the HCl salt by dissolving 16 μl of acetyl chloride in 5.0 ml of MeOH and adding this solution to the product, then concentrating to dryness.

C₁₉ H₂₄ N₄ O₂ * 1 HCl * 1 H₂ O M.W. 394.90.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.79  57.89                                                  Hydrogen         6.89   6.62                                                   Nitrogen         14.19  14.07                                                  Chlorine         8.98   9.06                                                   ______________________________________                                    

EXAMPLE 25 ##STR39##

4-fluoro-2-nitroaniline (15.6 g; 0.1 mole), 2,2-dimethoxypropane (24.6 ml; 0.2 mole) and trifluoroacetic acid [TFA] (23.1 ml; 0.005 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH₃ * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40% EtOAc/Hexane. Additional TFA, BH₃ * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-fluoro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with 10% methyl-t-butylether/hexane. The product was the first major component to elute, which produced 11.2 g (58%) of a yellow oil.

C₉ H₁₀ FN₂ O₂ M.W. 198.19.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           54.54  55.09                                                  Hydrogen         5.59   5.63                                                   Nitrogen         14.13  14.00                                                  ______________________________________                                    

EXAMPLE 26 ##STR40##

4-fluoro-N-isopropyl-2-nitroaniline (11.1 g; 0.0564 mole) was dissolved in MeOH (330 ml) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 1.5 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (200 ml) and triphosgene (5.6 g; 0.0566 mole) dissolved in 25 ml CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. and then concentrated. The solid was triturated with water and filtered, washed with Et₂ O and suction dried. 5.2 g (47.5%) of a purple-white solid.

C₁₀ H₁₁ FN₂ O * 0.1 H₂ O M.W. 197.8.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           61.28  61.06                                                  Hydrogen         5.76   5.52                                                   Nitrogen         14.29  14.22                                                  ______________________________________                                    

EXAMPLE 27 ##STR41##

4-methoxy-2-nitroaniline (16.8 g; 0.1 mole), 2,2-dimethoxypropane (24.6 ml; 0.2 mole) and trifluoroacetic acid [TFA] (23.1 ml; 0.005 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH₃ * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40% EtOAc/Hexane. Additional TFA, BH₃ * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-fluoro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with 10% methyl-t-butylether/hexane. The product was the first major component to elute, which produced 13.2 g (62%) of a yellow solid.

C₁₀ H₁₄ N₂ O₃ M.W. 210.22.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           57.13  57.15                                                  Hydrogen         6.71   6.78                                                   Nitrogen         13.32  13.33                                                  ______________________________________                                    

EXAMPLE 28 ##STR42##

N-isopropyl-4-methoxy-2-nitroaniline (13.1 g; 0.0627 mole) was dissolved in MeOH (330 ml) and hydrogenated at room temperature, at 5.0 psi over Ra-Ni for 1.5 hr. at which time the theoretical hydrogen uptake had been achieved. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH₂ Cl₂ (250 ml) and triphosgene (6.3 g; 0.06447 mole) dissolved in 25 ml CH₂ Cl₂ was added. The reaction was exothermic. The reaction mixture was stirred for 1 hr. then concentrated. The solid was triturated with water and filtered, washed with Et₂ O and suction dried. 9.9 g (76%) of a purple-white solid.

C₁₁ H₁₄ N₂ O₂ * 0.1 H₂ O M.W. 208.05.

    ______________________________________                                         Elements         Calc   Found                                                  ______________________________________                                         Carbon           63.51  63.31                                                  Hydrogen         6.88   6.93                                                   Nitrogen         13.46  13.42                                                  ______________________________________                                    

The benzimidazolone compounds of Examples 26 and 28 can be used to prepare the compounds of the claimed invention in a manner similar to that of Examples 12-24.

BEZOLD-JARISCH REFLEX

The compound to be evaluated was administered i.p. (mg/kg) to a group of 3 mice. Thirty minutes later, a 5-HT (0.25 mg/kg i.v.)-induced bradycardia was recorded in pentobarbital anesthetized animals. A greater than 50 percent (>50) reduction in the bradycardic response relative to vehicle-treated control mice was considered significant.

This method has been described by Saxena, P. R. and Lawang, A., Arch. Int. Pharmacodyn., 277:235-252, 1985.

The assay results for the compounds of the present invention and their Minimum Effective Dose (MED) and the reference compounds and their MEDs are recorded in Table I.

                  TABLE I                                                          ______________________________________                                                       Minimum Effective Dose                                           COMPOUND      (MED) mg/kg                                                      ______________________________________                                         Example 13    10                                                               Example 23    1                                                                BRL-43694     0.05                                                             cisapride     5                                                                cyproheptadine                                                                               5                                                                domperidone   >10                                                              GR-38032      0.5                                                              ketanserin    >10                                                              mecamylamine  2.5                                                              methylsergide >10                                                              metoclopramide                                                                               5                                                                scopolamine   2.5                                                              ______________________________________                                    

SEROTONIN (5-HT₃)

Procedure

GR65630 binds to the 5-HT₃ receptor. Brain cortices were obtained from male rats and a membrane fraction prepared by standard techniques. 0.04 mg of membrane prep was incubated with 0.2 nM [³ H]-GR656630 for 60 minutes at 22° C. Non-specific binding was estimated in the presence of 1 uM ICS 205-930. Membranes were filtered and washed 3 times and the filters were counted to determine [³ H]-GR65630 specifically bound. Kilpatrick G. J., Jones B. J. and Tyers M. B. Identification and distribution of 5-HT₃ receptors in rat brain using radioligand binding assay. Nature, 330: 746-748, 1987.

Results

Kd=2.46 nM

Bmax=154 fmol/mg protein

% Specific Binding: 70

                  TABLE II                                                         ______________________________________                                         Effect of Compounds on                                                         [H]-GR65630 Bound (0.2 nM)                                                     Compound          Ki                                                           ______________________________________                                         Quipazine         0.18        nM                                               ICS 205-930       0.51        nM                                               5-HT              0.39        uM                                               RU24969           1.85        uM                                               Zacopride         0.18        nM                                               Example 12        2,800       nM                                               Example 13        120         nM                                               Example 14        36          nM                                               Example 15        92          nM                                               Example 16        1,200       nM                                               Example 17        41% @ 10,000                                                                               nM                                               Example 18        1,200       nM                                               Example 19        1,200       nM                                               Example 20        19          nM                                               Example 21        55          nM                                               Example 22        360         nM                                               Example 22B       4.9         nM                                               Example 23        75          nM                                               Example 24        2.0         nM                                               ______________________________________                                    

IN VITRO FUNCTIONAL ASSAY FOR SEROTONIN 5-HT₄ AGONISM: RAT TMM

Serotonin 5-HT₄ agonism was measured in the rat esophagus in vitro preparation as reported by Baxter et al (Naunyn. Schmied. Arch. Pharmacol. 1991, 343, 439). Agonist activity was determined utilizing relaxation of carbachol-contracted rat tunica muscularis mucosas. One 2 cm segment of intrathoracic esophagus proximal to the diaphragm was removed from male rats, weighing approximately 300 gm, and the outer muscle layers removed. The inner tunica muscularis mucosa was mounted under 0.2-0.3 g of tension in a tissue bath containing oxygenated Tyrodets solution at 37° C. Cortisterone acetate (30 μM) and fluoxetine (1 μM) were included in the buffer to prevent uptake of serotonin, as well as pargyline (10 μM) to inhibit monoamine oxidase. Following a 30 min equilibrium period, tissues were isometrically contracted with carbachol (3 μM) to obtain a tonic contraction. A stable plateau was obtained within 20 min when test compound was added cumulatively to relax the muscle strip. EC50 values were obtained for each agonist in tissues from 5 rats. EC50 values for agonists at this 5-HT₄ receptor are indicated in Table III.

                  TABLE III                                                        ______________________________________                                                        5-HT.sub.4 Agonism (Rat TMM) In                                 Compound       Vitro Assay: EC50 Values                                        ______________________________________                                         Serotonin      9           nM                                                  Example 12     9467        nM                                                  Example 13     179         nM                                                  Example 14     3833        nM                                                  Example 15     4584        nM                                                  Example 16     10000       nM                                                  Example 20     10000       nM                                                  Example 21     2135        nM                                                  Example 23     374         nM                                                  Example 24     1506        nM                                                  ______________________________________                                    

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention. 

What is claimed is:
 1. A compound of the formula ##STR43## or a pharmaceutically acceptable salt thereof wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino;R₃ is selected from the group consisting of H, alkyl and cycloalkyl; X is NH or O; Z is selected from the group consisting of ##STR44## n is 1 or
 2. 2. A compound according to claim 1 wherein Z is ##STR45##
 3. A compound according to claim 2 wherein X is NH.
 4. A compound according to claim 3 which is N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-4a-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 5. A compound according to claim 1 wherein Z is ##STR46##
 6. A compound according to claim 5 wherein X is NH.
 7. A compound according to claim 1 wherein Z is ##STR47##
 8. A compound according to claim 7 wherein X is NH.
 9. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 10. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 11. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 12. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 13. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 14. A compound according to claim 8 which is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl) -3-ethyl-2,3-dihydro-2-oxo-1H-benzisidazole-1-carboxamide.
 15. A compound according to claim 8 which is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 16. A compound according to claim 8 which is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 17. A compound according to claim 8 which is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 18. A compound according to claim 8 which is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 19. A compound according to claim 8 which is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 20. A pharmaceutically composition comprising a therapeutically effective amount of a compound of the formula ##STR48## or a pharmaceutically acceptable salt thereof wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino,monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino; R₃ is selected from the group consisting of H, alkyl and cycloalkyl; X is NH or O; Z is selected from the group consisting of ##STR49## n and r are independently 1 or 2; p is 0 or 1; and a pharmaceutically acceptable carrier.
 21. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 22. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 23. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 24. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 25. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 26. A pharmaceutical composition according to claim 20 wherein the compound is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl) -3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 27. A pharmaceutical composition according to claim 20 wherein the compound is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 28. A pharmaceutical composition according to claim 20 wherein the compound is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-5-chloro-3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide.
 29. A pharmaceutical composition according to claim 20 wherein the compound is endo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 30. A pharmaceutical composition according to claim 20 wherein the compound is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl) -2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 31. A pharmaceutical composition according to claim 20 wherein the compound is exo-N-(1-azatricyclo[3.3.1.1³,7 ]decan-4-yl)-6-chloro-2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-benzimidazole-1-carboxamide.
 32. A method of treating conditions responsive to treatment with 5-HT₄ and 5-HT₃ agents comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula ##STR50## or a pharmaceutically acceptable salt thereof wherein R₁ and R₂ are independently selected from the group consisting of hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino;R₃ is selected from the group consisting of H, alkyl and cycloalkyl; X is NH or O; Z is selected from the group consisting of ##STR51##
 33. A method according to claim 32 wherein the condition is treatable with a serotonin 5-HT₄ agonist.
 34. A method according to claim 33 wherein the condition is selected from the group consisting of esophagitis, non-ulcer dyspepsia, gastroparesis, ileus, constipation predominant irritable bowel syndrome, constipation and cognitive dysfunction.
 35. A method according to claim 32 wherein the condition is treatable with a serotonin 5-HT₄ antagonist.
 36. A method according to claim 35 wherein the condition is selected from the group consisting of diarrhea or diarrhea predominant irritable bowel syndrome.
 37. A method according to claim 32 wherein the condition is treatable with a serotonin 5-HT₃ antagonist.
 38. A method according to claim 37 wherein the condition is selected from the group consisting of emesis, anxiety, cognitive disorders, drug abuse and diarrhea predominant irritable bowel syndrome. 